1. Technical Field
The invention relates to an improved process for the preparation of certain macrocyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections, or as intermediates useful in preparing such agents.
2. Background Information
The macrocyclic compounds of the following formula (I) and methods for their preparation are known from: Tsantrizos et al., U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application Publication No. 2003/0224977 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0075279 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0080005 A1; Brandenburg et al., U.S. Application Publication No. 2005/0049187 and Samstag et al., U.S. Application Publication No. 2004/0248779 A1:
whereinRA is OH, O-PG, where PG is a protecting group, or —OSO2—R27, wherein R27 is selected from phenyl, p-tolyl, p-bromophenyl, p-nitrophenyl, methyl, trifluoromethyl, perfluorobutyl and 2,2,2-trifluoroethyl;or a group of formula II
W is CH or N;L0 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S—C1-4alkyl (the sulfur being in any oxidized state); orL0 and L1 orL0 and L2 may be covalently bonded to form together with the two C-atoms to which they are linked a 4-, 5- or 6-membered carbocyclic ring wherein one or two (in the case of a 5- or 6-membered ring) —CH2— groups not being directly bonded to each other, may be replaced each independently by —O— or NRa wherein Ra is H or C1-4alkyl, and wherein said ring is optionally mono- or di-substituted with C1-4 alkyl;R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;said cycloalkyl, aryl or Het being substituted with R24,wherein R24 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH—C(O)—R25; or NH—C(O)—NH—R25, wherein each R25 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;or R24 is NH—C(O)—OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl;R3 is hydroxy, NH2, or a group of formula —N(R*)—R9, wherein R* is H or a protecting group, and R9 is C6 or 10 aryl,heteroaryl, —C(O)—R20, —C(O)—NHR20 or —C(O)—OR20, wherein R20 is C1-6 alkyl or C3-6 cycloalkyl;D is a 3 to 7 atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S or N—R27, wherein R27 is H, C1-6alkyl, C3-6cycloalkyl or C(O)R28, wherein R28 is C1-6alkyl, C3-6cycloalkyl or C6 or 10 aryl;R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl; andA is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl, C7-16 aralkyl, or SO2R5A wherein R5A is C1-8 alkyl, C3-7 cycloalkyl, C1-6 alkyl-C3-7 cycloalkyl;or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C viral (HCV) infections, or as intermediates useful for the preparation of such anti-HCV agents as described therein, and are prepared therein via ring-closing metathesis of an acyclic diolefin using ruthenium-based catalysts in a suitable organic solvent. The disadvantages of the previously reported approaches to the compound (I) via ring-closing metathesis include long reaction time, high catalyst loading, moderate yields, and the need to use lower concentrations of the diene substrate to obtain optimum results. Thus, there is a continuing need in the art to develop improved processes for obtaining the macrocyclic compounds of formula (I).